CASE REPORT Open Access

Liver resection for HER2-enriched breastcancer metastasis: case report and reviewof the literatureMai Temukai1, Hajime Hikino1*, Yoshinari Makino1 and Yoko Murata2

Abstract

Liver metastasis from breast cancer usually results in the development of systemic metastasis. We reporta breast cancer patient with an early isolated liver recurrence who survived more than 7 years with norecurrence. She was treated with aggressive HER2-directed chemotherapy and hepatic metastasectomy.Local hepatectomy with effective medical oncological therapy with curative intent is worth trying inpatients with breast cancer liver metastasis.

Keywords: Breast cancer, Liver metastasis, Hepatectomy

BackgroundThe liver is the primary site of recurrence in 12–15% ofbreast cancer patients [1]. Under routine imagingworkup such as positive emission tomography (PET)and computed tomography (CT), the incidence of anisolated liver metastasis has been reported as approxi-mately 0.9% among patients who underwent breastcancer surgery [2]. Even in patients with an isolated livermetastasis at the first presentation, breast cancer livermetastasis (BCLM) is usually part of generalized meta-static disease, resulting in the development of systemicmetastasis. If treated with chemotherapy, the mediansurvival of breast cancer patients with only liver metas-tasis or with limited disease elsewhere is 19 to 26 months[3]. For the select subset of patients presenting withisolated BCLM, hepatic metastasectomy has been proposedas a useful treatment associated with a good outcome [4].However, the strategy of hepatic metastasectomy in BCLMis still debatable. We present a patient who developed asolitary BCLM as the first recurrence and yet achievedlong-term disease-free survival after aggressive humanepidermal growth factor receptor 2 (HER2)-directedchemotherapy and hepatic metastasectomy.

Case presentationA 56-year-old woman was referred to our hospital witha 1-month history of a lump in her left breast. Physicalexamination revealed a 4.0 × 3.0-cm tumor in the lowerouter quadrant of the left breast. Biopsy specimen bycore needle biopsy from the left breast lump showed aninvasive ductal carcinoma that was both estrogen recep-tor (ER)- and progesterone receptor (PgR)-negative witha HER2 of 3+ by immunohistochemistry assay. A PET/CT scan showed uptake of 18F-fluorodeoxyglucose onlyin the left breast tumor and the left axillary lymphnodes, but not in distant organs. The patient was diag-nosed with primary breast cancer (cT2N1M0 stage IIBaccording to the Union for International Cancer Control(UICC) classification).She received preoperative chemotherapy consisting of

paclitaxel (80 mg/m2) weekly for 12 weeks, followed by5-fluorouracil, epirubicin, and cyclophosphamide (FEC)(500/100/500 mg/m2) four times every 3 weeks. Follow-ing preoperative chemotherapy, physical examinationrevealed only induration of the left breast. Preoperativechest and abdominal CT scanning with contrast mediumshowed no signs of distant metastasis.The patient underwent a modified radical mastectomy

of the left breast. Pathological evaluation confirmedresidual invasive ductal carcinoma within the breasttissue (ER- and PgR-negative, HER2 3+) and metastaticcarcinoma within three dissected axillary lymph nodes.

* Correspondence: hikino_hajime@matsue.jrc.or.jp1Department of Breast Surgery, Matsue Red Cross Hospital, 200 Horo, Matsue,Shimane 690-8506, JapanFull list of author information is available at the end of the article

© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made.

Temukai et al. Surgical Case Reports (2017) 3:33 DOI 10.1186/s40792-017-0307-1

Following surgery, the patient received weekly trastu-zumab monotherapy (initially 4 mg/kg, followed by twoor more cycles of 2 mg/kg) as adjuvant treatment. Threemonths after the start of trastuzumab, the patient’sserum HER2 level had increased to 17.6 ng/ml (normalrange <15.2 ng/ml). Metastatic workup with PET/CTscan and sonography of the liver revealed an isolatedliver metastasis (segment IV, 16 × 18 mm in diameter)(Fig. 1). Weekly trastuzumab and vinorelbine ditartrate(25 mg/m2, day 1, 8, every 3 weeks) were administeredas the first-line treatment, but the tumor did not re-spond. Then, weekly trastuzumab and triweekly doce-taxel (60 mg/m2) were administered as the second-linetreatment. However, 2 months later, the liver metastasishad progressed. We modified the chemotherapeutic regi-men to oral capecitabine (1650 mg/m2, day 1–14, every21 days) along with trastuzumab and triweekly docetaxelas the third-line treatment. After 4 cycles of this chemo-therapy, CT scanning showed that the size of the livermetastasis had decreased. However, soon after, progres-sion of the remaining liver metastasis was anticipatedfrom her clinical course.After adequate informed consent, the patient under-

went partial resection of the liver (R0) (Fig. 2). Thetumor was consistent with liver metastasis (7 × 9 mm)from breast cancer and showed the same pathologicalcharacteristics: ER- and PgR-negative, HER2 3+. Afterliver metastasectomy, the patient was administered acombined chemotherapy regimen of weekly trastuzumaband oral capecitabine. Two months later, her cardiacfunction had deteriorated as an adverse effect of thechemotherapy. Although she has not been treated there-after, no local recurrence or other distant metastaseshave appeared for more than 7 years.

DiscussionThe patient described here had favorable long-termsurvival after diagnosis of liver metastasis, which maydemonstrate that a select group of patients with isolatedliver metastasis can benefit from aggressive systemicHER2-directed chemotherapy and complete surgical re-section, even without continuous chemotherapy.Weichselbaum and Hellman proposed that a state of

oligometastasis may exist in which the metastases arelimited in number and site [5]. Good outcome has beenobserved in patients treated with local therapy for oligo-metastasis. Although local hepatectomy is possible forsolitary BCLM, many patients develop recurrent disease[4]. In a study by Lermite et al., liver recurrences werediagnosed at a mean interval of 15 months post-hepatectomy and extrahepatic recurrences at 22 months[6]. Ruiterkamp and Ernst found that in 13–56% of allcases in their study, the first location of recurrence wasin the remaining liver [7]. It is not possible to predictthe subsequent clinical course of disease, or to deter-mine whether the presence of limited liver metastasisrepresents a true state of oligometastasis or a transi-tional state to disseminated metastasis. In the presentcase, early hepatic recurrence developed at 3 monthsafter mastectomy—during adjuvant trastuzumab thera-py—fitting into the latter scenario. Achievement of onlylocal control of liver metastasis could rarely be “cura-tive.” Co-administration of effective medical oncologicaltherapy may be needed for long-term survival.In the literature, several independent factors have been

proposed that might influence the prognosis of breastcancer patients after liver metastasectomy (Table 1). Aliterature search was performed through the MedicalLiterature Analysis and Retrieval System Online (MED-LINE) database. Fisher et al. first reported in 1990 the

Fig. 1 Abdominal computed tomography. Postoperative abdominalcomputed tomography revealed an ill-defined mass (white arrow),16 × 18 mm in diameter, on liver segment IV

Fig. 2 Gross view of liver tumor. Gross view of liver tumor (whitearrowheads) shows a yellowish-white, elastic-hard solid component,7 × 9 mm in diameter

Temukai et al. Surgical Case Reports (2017) 3:33 Page 2 of 5

efficacy of the Adriamycin and cyclophosphamide (AC)regimen, which today is one of the main prescribedchemotherapy regimens for breast cancer [8]. Therefore,we selected reports that were published after 1990. As ageneral problem, most published studies are designed asretrospective single-arm and single-center analyses, ana-lyzing data of only small sample sizes that were collectedover periods of ≥10 years. Our literature search showedthat there is no clear consensus on selection criteria forreferral of patients for liver metastasectomy.With this background, most authors have described

achievement of R0 (complete macroscopic and micro-scopic) resection as the main prognostic factor for breast

cancer patients after liver metastasectomy [9, 10]. Twoselection criteria for patients to be accepted for curativehepatic resection are, first, the absence of extrahepaticdisease (with the exception of isolated pulmonary andbony metastases) and, second, the ability of the surgeonto perform an R0 resection with a low risk of morbidity[11]. Furthermore, solitary liver metastasis is a signi-ficant prognostic factor [12–14]. Preoperative detailedexploration using multislice CT, contrast-enhanced MRI,or PET scan should be mandatory to minimize unneces-sary surgery and maximize survival benefit.The second prognostic factor for breast cancer pa-

tients after liver metastasectomy is a long interval (more

Table 1 Prognostic factors of overall survival in patients after liver metastasectomy from breast cancer. (only multivariate Coxregression analyses)

Study Hoffman10 Abott15 Walsum12 Zegarac13 Dittmar16 Weinrich9 Vertriest14

Number 41 86 32 32 34 21 27

Duration 1999–2008 1997–2010 1991–2011 2006–2009 1997–2010 2001–2007 1996–2013

Median overall survival (months) 58 57 55 37 36 53 116

5-year overall survival (%) 48.4 37 28 33 78

Median disease-free survival (months) 34 14.2 11 22.5

5-year disease-free survival (%) 31 19 36

Characteristics of primary BC

ER status p = 0.009 p < 0.05

(pos) (pos)

Lymph node status p < 0.05

(neg)

Tumor size p < 0.05

(<3 cm)

Grading p = 0.0059

Stage p = 0.03

(Stages I–II)

Characteristics of LM and LM treatment

Age p = 0.004

(<50)

Period from BC to LM p = 0.0097 p < 0.05

(>24 months) (>24 months)

Number of LM p < 0.05 p < 0.01 p = 0.04

(1 vs >1) (1 vs >1) (1 vs >1)

HER2 status p = 0.010

(pos)

Absence of extrahepatic tumor p = 0.042

Response to preoperative chemotherapy p = 0.003

(good response)

Resection margins p = 0.0015

(R0 vs R1/2)

BC breast cancer, ER estrogen receptor, LM liver metastasis, HER2 human epidermal growth factor receptor 2, neg negative, pos positive, R0 complete microscopicresection, R1 microscopic residual disease, R2 macroscopic residual hepatic or extrahepatic disease

Temukai et al. Surgical Case Reports (2017) 3:33 Page 3 of 5

than 1 year) between diagnosis of breast cancer anddetection of liver metastasis [6, 7, 10, 13]. Several studieshave found that patients with ER- and/or PgR-positiveBCLM are good candidates for liver metastasectomy dueto favorable tumor biology and administration of hor-mone therapy [13, 15]. Such characteristics of primarybreast cancer as small tumor size, node negativity, lowgrade and early stage may also be associated with betteroutcome after liver metastasectomy [9, 13, 14]. On theother hand, patients with triple negative phenotype inthe primary breast cancer and/or liver metastases maynot benefit from liver metastasectomy due to aggressivebiological behavior and limited treatment strategies.The third factor proposed as influencing the prognosis

of breast cancer patients after metastasectomy is re-sponse to preoperative systemic therapy [15]. If systemictherapy can eradicate microscopic metastatic tumor inremnant liver and systemic organs, aggressive local ther-apies to treat limited BCLM may translate into improvedsurvival. The response may also serve as a guide forfurther postoperative therapy. On the other hand, thepatient who has not demonstrated disease regression orstability with systemic chemotherapy may not be a candi-date for liver metastasectomy. Overexpression of HER2 onhepatic metastases may be correlated with improved sur-vival [16, 17]. Pooled discordance proportion between pri-mary and recurrent breast cancer was reported in 8% ofpatients with HER2, 20% of patients with ER, and 33% ofpatients with PgR by a meta-analysis [18]. Furthermore, itis suggested that the mutation of the metastatic phenotypeis lower at earlier recurrence sites. Actually, no biologicalchange was demonstrated between primary and corre-sponding asynchronous liver metastasis in the presentpatient. Response-guided chemotherapy for liver metastasismay also be effective in systemic micro-metastasis, contrib-uting to long-term survival with no continuous chemother-apy. Because of remarkable progress in the effectiveness ofHER2-directed therapy, the use of local therapy to treatlimited BCLM may expand further in patients with overex-pression of HER2 on hepatic metastases [6].

ConclusionsLiver metastasectomy may offer a survival advantageover systemic chemotherapy alone in select patients withBCLM. However, independent prognostic factors pre-dictive for survival are still not clearly defined. Furtherstudies are needed to identify a subgroup of patientswho may benefit from aggressive multidisciplinary treat-ment including liver metastasectomy.

AbbreviationsBCLM: Breast cancer liver metastasis; ER: Estrogen receptor; HER2: Humanepidermal growth factor receptor 2; PgR: Progesterone receptor

FundingThere is no funding for this work.

Authors’ contributionsAll authors conceived of the study and participated in its design and helpedto draft the manuscript. HH checked and revised the manuscript. All authorsread and approved the final manuscript.

Competing interestsThe authors declare that they have no competing interests.

Consent for publicationWritten informed consent was obtained from the patient for publication ofthis case report and any accompanying images. A copy of the writtenconsent is available for review by the Editor-in-Chief of this journal.

Author details1Department of Breast Surgery, Matsue Red Cross Hospital, 200 Horo, Matsue,Shimane 690-8506, Japan. 2Department of Breast and Endocrine Surgery,Tottori University, 36-1, Nishimachi, Yonago, Tottori 683-8504, Japan.

Received: 23 October 2016 Accepted: 14 February 2017

References1. Pivot X, Asmar L, Hortobagyi GN, Theriault R, Pastorini F, Buzdar A. A

retrospective study of first indicators of breast cancer recurrence. Oncology.2000;58:185–90.

2. Kim JY, Park JS, Lee SA, Kim JK, Jeong J, Yoon DS, et al. Does liver resectionprovide long-term survival benefits for breast cancer patients withlivermetastasis? A single hospital experience. Yonsei Med J. 2014;55:558–62.

3. Singletary SE, Walsh G, Vauthey JN, Curley S, Sawaya R, Weber KL, et al.A role for curative surgery in the treatment of selected patients withmetastatic breast cancer. Oncologist. 2003;8:241–51.

4. Bergenfeldt M, Jensen BV, Skjoldbye B, Nielsen D. Liver resection and localablation of breast cancer liver metastases—a systematic review. Eur J SurgOncol. 2011;37:549–57.

5. Weichselbaum RR, Hellman S. Oligometastases revisited. Nat Rev Clin Oncol.2011;8:378–82.

6. Lermite E, Marzano E, Chéreau E, Rouzier R, Pessaux P. Surgical resection ofliver metastases from breast cancer. Surg Oncol. 2010;19:e79–84.

7. Ruiterkamp J, Ernst MF. The role of surgery in metastatic breast cancer.Eur J Cancer. 2011;47 Suppl 3:S6–22.

8. Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG,et al. Two months of doxorubicin-cyclophosphamide with and withoutinterval reinduction therapy compared with 6 months ofcyclophosphamide, methotrexate, and fluorouracil in positive-nodebreast cancer patients with tamoxifen-nonresponsive tumors: resultsfrom the National Surgical Adjuvant Breast and Bowel Project B-15.J Clin Oncol. 1990;8:1483–96.

9. Weinrich M, Weiß C, Schuld J, Rau BM. Liver resections of isolated livermetastasis in breast cancer: results and possible prognostic factors. HPBSurg. 2014;2014:893829. doi:10.1155/2014/893829.

10. Hoffmann K, Franz C, Hinz U, Schirmacher P, Herfarth C, Eichbaum M, et al.Liver resection for multimodal treatment of breast cancer metastases:identification of prognostic factors. Ann Surg Oncol. 2010;17:1546–54.

11. Howlader M, Heaton N, Rela M. Resection of liver metastases from breastcancer: towards a management guideline. Int J Surg. 2011;9:285–91.

12. van Walsum GA, de Ridder JA, Verhoef C, Bosscha K, van Gulik TM, HesselinkEJ, et al. Resection of liver metastases in patients with breast cancer: survivaland prognostic factors. Eur J Surg Oncol. 2012;38:910–7.

13. Zegarac M, Nikolic S, Gavrilovic D, Jevric M, Kolarevic D, Nikolic-Tomasevic Z,et al. Prognostic factors for longer disease free survival and overall survivalafter surgical resection of isolated liver metastasis from breast cancer.J BUON. 2013;18:859–65.

14. Vertriest C, Berardi G, Tomassini F, Vanden Broucke R, Depypere H,Cocquyt V, et al. Resection of single metachronous liver metastasesfrom breast cancer stage I–II yield excellent overall and disease-freesurvival. Single center experience and review of the literature. Dig Surg.2015;32:52–9.

Temukai et al. Surgical Case Reports (2017) 3:33 Page 4 of 5

15. Abbott DE, Brouquet A, Mittendorf EA, Andreou A, Meric-Bernstam F, ValeroV, et al. Resection of liver metastases from breast cancer: estrogen receptorstatus and response to chemotherapy before metastasectomy defineoutcome. Surgery. 2012;151:710–6.

16. Dittmar Y, Altendorf-Hofmann A, Schüle S, Ardelt M, Dirsch O, RunnebaumIB, et al. Liver resection in selected patients with metastatic breast cancer: asingle-centre analysis and review of literature. J Cancer Res Clin Oncol. 2013;139:1317–25.

17. Martinez SR, Young SE, Giuliano AE, Bilchik AJ. The utility of estrogenreceptor, progesterone receptor, and Her-2/neu status to predict survival inpatients undergoing hepatic resection for breast cancer metastases. AmJ Surg. 2006;191:281–3.

18. Aurilio G, Disalvatore D, Pruneri G, Bagnardi V, Viale G, Curigliano G, et al.A meta-analysis of oestrogen receptor, progesterone receptor and humanepidermal growth factor receptor 2 discordance between primary breastcancer and metastases. Eur J Cancer. 2014;50:277–89.

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